Isotretinoin Use and Liver Enzymes Changes: A Single-Center Study in Saudi Arabia

Introduction Isotretinoin is a bioactive retinoic acid variant that is taken orally to treat moderate to severe acne vulgaris. One of the adverse effects of isotretinoin is elevated liver enzymes. This study estimated the prevalence of liver enzyme changes during isotretinoin use among dermatology clinic patients in Al-Ahsa, Kingdom of Saudi Arabia. Methods This study was a retrospective analysis that reviewed the medical data of 97 patients with acne at the King Faisal University Polyclinic who were taking systemic isotretinoin. It determined the baseline, second, and last readings of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Among the 97 patients, 67 (69.1%) were female and 30 (30.9%) were male. Results Of the patients, 41 (50.6%) weighed 51-70 kg, and 45 (46.4%) were 21-23 years old. The age of acne onset was 20 years or younger. Most patients had a starting isotretinoin dose of 10-20 mg and an ending dose of 30-40 mg over six months. Ninety (92.8%) patients had not used isotretinoin in the past. Before treatment, AST was elevated in three (3.1%) patients, and ALT was elevated in two (2.1%) patients. In the last readings, AST was elevated in eight (8.2%) patients, and ALT was elevated in four (4.1%) patients. Conclusion The result of this study indicates that the incidence of high levels of AST and ALT with oral isotretinoin was low. So frequent laboratory monitoring is not recommended since the elevation was not associated with any morbidity and carries financial and emotional burdens. An exception is patients with higher body weight, males, and those whose acne started at age 16-19, in whom frequent monitoring may be considered for AST more than ALT.


Introduction
Isotretinoin is an active form of retinoic acid derived from vitamin A that predominantly affects the lipid composition of the skin by decreasing sebaceous gland size and sebum production [1].
There is a recent hypothesis that taking isotretinoin orally increases the expression of the transcription factor p53. Increasing the expression of p53 regulates many transcription factors implicated in the development of acne vulgaris, including FoxO1, androgen receptor, and key genes involved in autophagy and apoptosis induction [2].Regarding the dosage, a recent systemic review showed that severe acne reacts better to standard (0.5 mg/kg/day) or higher fixed daily dosages of isotretinoin (1.6 mg/kg/day) [3].
Acne is a common inflammatory skin condition that affects the skin's pilosebaceous units [4,5].Isotretinoin is indicated for treating moderate to severe acne that is unresponsive to other therapies [2,6].An adequate treatment course can induce remission by regulating cell division and differentiation and inhibiting sebum production [7].
Isotretinoin is linked to several side effects of which teratogenicity is the most harmful.However, dry, cracked lips, skin, and nasal mucosa are the most common mucocutaneous side effects [8,9].Increased levels of liver enzymes including aspartate transaminase (AST) and alanine transaminase (ALT) and lipid changes including changes in triglyceride (TG) and total cholesterol (TC) levels are other adverse effects linked to systemic isotretinoin [10,11].Local studies have identified elevated AST and ALT levels in laboratory monitoring during acne treatment [12,13].
Studies have reported conflicting findings on the prevalence of isotretinoin-associated liver enzyme changes.Because of the lack of consensus, we analyzed the prevalence of liver enzyme changes in patients who were prescribed isotretinoin at the King Faisal University (KFU) Polyclinic in Al-Ahsa, Saudi Arabia.

Materials And Methods
This study adopted a retrospective cohort design and collected patient data and laboratory test results from the KFU Polyclinic's recording system.Before starting the study, ethical approval was obtained from the KFU Research Ethics Committee (approval number: KFU-REC-2023-SEP-ETHICS1107 dated September 6, 2023).The study included patients with acne vulgaris of all ages who received oral isotretinoin therapy along with baseline and follow-up lab testing to assess AST and ALT levels.Those who used isotretinoin for medical conditions other than acne and those who had only one or two readings were excluded from the study.
The following parameters were assessed: age, gender, weight, age of acne onset, age at which isotretinoin treatment began, dose of isotretinoin (starting dose and ending dose), duration of treatment, previous isotretinoin use, and liver enzymes lab test results.
Patients were regularly monitored; the laboratory findings of the AST and ALT levels were collected before the start of the treatment with isotretinoin (pre-treatment) and during the treatment.In this study, we considered three readings: the pre-treatment reading, one to three months after the start of the treatment, and four to six months after the start of the treatment (second and last readings).According to the analyzing reference laboratory, AST levels of 14-36 uIU/L were classified as normal and levels >36 uIU/L were classified as high.ALT levels of 9-52 U/L were classified as normal and levels >52 U/L were classified as high.
Data were entered into a Microsoft Excel document (Microsoft Corporation, Redmond, Washington, United States).Categorical variables are presented as numbers and percentages.Fischer Exact Test was used to identify the relationship between the patient's demographic and clinical characteristics with the normal and the abnormal liver enzyme levels.Statistical significance was defined as a p-value less than or equal to 0.05.The data were analyzed using IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States).

Results
A total of 97 patients with liver enzyme data were included in the study.Among them, 45 (46.4%) were between the ages of 21 and 23 years, and most patients were female (n=67; 69.1%).Approximately half (n=42; 50.6%) of the patients weighed 51-70 kg.Nearly half of the patients (n=48; 49.5%) began isotretinoin treatment at age 20 or younger, and the most common age of acne onset was 19 years or older (n=47; 48.5%).The starting dose was typically 10-20 mg in 85 (87.6%) patients, whereas the ending dose was typically 30-40 mg in 49 (50.5%)patients.Most patients (n=52; 53.6%) had a treatment duration of six months, and seven (7.2%) patients had used isotretinoin previously (Table 1).

TABLE 3: Relationship between first and last AST readings and the demographic and clinical characteristics of the patients (N = 97)
AST: aspartate aminotransferase p-values were calculated using the Fisher exact test.
** Significant at p < 0.05 level Furthermore, we did not observe significant relationships between pre-treatment ALT levels and any of the demographic or clinical characteristics (all p > 0.05) except for a relationship between male gender and high ALT levels in the last readings (p = 0.008) (Table 4).

Discussion
Previous studies have identified changes in liver enzyme (AST and ALT) levels as a side effect of oral isotretinoin treatment [10,12].Some studies have reported a mild to moderate increase in liver enzymes as the most common side effect [14], whereas others have reported no elevation in liver enzymes [15].
Our study investigated the prevalence of liver enzyme changes during isotretinoin use in patients with acne.In pre-treatment, second, and last readings, the prevalence rates of AST elevation were 3 (3.1%),7 (7.2%), and 8 (8.2%), respectively, and the rates of elevated ALT levels were 2 (2.1%), 5 (5.2%), and 4 (4.1%),respectively.A recent retrospective study of 143 individuals with moderate or severe acne vulgaris who used oral isotretinoin reported similar findings: AST levels were higher in the second and last readings compared with the baseline, whereas ALT levels did not change significantly [16].In another recent study, including 200 patients, 20 (10%) and 15 (7.5%) patients exhibited elevated AST and ALT levels at baseline, respectively, followed by 30 (15%) and 40 (20%) patients in the third month and 91 (45.5%) and 20 (10%) patients in the sixth month [17].
In the present study, male gender was associated with elevated pre-treatment AST levels and last ALT readings.Similarly, another study reported a higher prevalence of liver abnormalities in males than in females [14].However, according to a different study, gender was not significantly associated with AST or ALT levels [16].
Our results showed no significant association between the dose and duration of treatment and AST and ALT levels; earlier studies have reached similar conclusions, demonstrating that dose and duration of treatment were not significantly associated with increased liver enzyme levels [8,12,14].In contrast to this, Abd-Elaziz et al. indicated that the dose of isotretinoin and duration of treatment were significantly associated with changes in AST and ALT levels.Patients who took 80 mg/day and used oral isotretinoin for four to six months were more likely to have increased liver enzymes [18].

TABLE 1 : Demographic and clinical characteristics of the patients (N = 97)
Pre-treatment AST and ALT levels were normal in 94 (96.9%) and 95 (97.9%) patients, respectively.The second AST and ALT readings (during the first to the third month) were normal in 90 (92.8%) and 92 (94.8%) patients, respectively, whereas the last readings (during the fourth to the sixth month) were normal in 89 (91.8%) and 93 (95.9%) patients, respectively (Table2).